Abstract In mammals, male X hemizygosity neccesitates dosage compensation of X-linked genes by means of X chromosome inactivation (XCI) in XX females. Because either X chromosome can be silenced, heterozygous females are typically mosaic for expression of parental alleles and therefore less susceptible to X-linked disorders than hemizygous males. When XCI is skewed however, disease penetrance rises with the fraction of cells that have silenced the functional allele. As a result, both males and females are exposed to the cumulative burden of monogenic disease harbored on the X chromosome. Yet, the inactive X chromsome (Xi) is not entirely silent: some genes, in particular those with paralogous copies on the Y chromosome (X-Y gene pairs), are exempt from dosage compensation and escape XCI. Turner syndrome (TS, karyotype 45,X) reflects a sensitivity to the dosage of such ?escapee? genes, and adds to the significant X-linked health burden through cardiovascular and renal malformations, as well as high rates of spontaneous termination of 45,X conceptuses. Much of the XCI field has focused on implicating and dissecting requisite gene silencing pathways, using the mouse X as the primary model. In contrast, the mechanism(s) that enable escapees to sustain expression from an otherwise repressed chromosome territory have received little attention, especially in humans. As a result, the identity, lineage-specificity, and regulatory mechanisms of escapees remain unresolved. Building on our allele-specific genomics and XCI expertise, we propose to address these questions in otherwise isogenic 45,X/46,XX human pluripotent stem cells. This platform will enable us to 1.) quantify allele-specific expression across the human X and along distinct cell lineages, 2.) dissect the local and long-range regulatory logic of escapees, and 3.) assess dosage-sensitive contributions of individual escapees. These advances will aid the interpretation of human X-linked variants, complement an expanding glossary of gene regulatory elements, and reveal how escapees manage to resist silencing. Such mechanstic insights may yield novel means of manipulating regulatory elements, and subsequently translate into generalized, epigenetic approaches to X-linked disease in heterozygous females, as well as gene dosage correction in TS and other dosage-sensitive disorders in the human genome.